Anesthetic combinations containing, besides a local anesthetic agent, a vasoconstricting agent



Patented Nov. 24, 1936 UNITED STATES 2,061,557 PATENT OFFICE ANESTHETICCOMBINATIONS CONTAINING, BESIDES A LOCAL ANESTHETIC AGENT, AVASOCONSTBIC'I'ING AGENT Max Bockmiihi, Frankfort-on-the-Main, and OttoSchaumann, .Wiesbaden, and Gustav Ehrhart and Leonhard Stein,Frankfort-on-the-Main,

Germany, assignors to Winthrop Chemical Company, Inc., New York, N. Y.,a corporation of New York No Drawing. Application March 16, 1934, SerialNo. 715,994. In Germany April 22, 1933 6 Claims.

HO CZECH-CZECH;

NH: HO

whereby the disadvantages of the local anesthetic combinations of thistype, which have hitherto been known and employed, are obviated.

It is known to employ local anesthetic combinations containing, besidesa local anesthetic agent, a vasoconstricting agent, the functions of thelatter being to localize and prolong the anesthesia. Thevasoconstricting agent, almost universally employed for this purpose, isepinephrin, i. e. 3.4-dihydroxy-phenyl-ethanol-methylamine of thefollowing formula:

HO CHOHJIJHX NH'CH; o

For example a commonly used anesthetic combination of this type containsa local anesthetic agent such as the monohydrochloride ofparaamino-benzoyl-diethyl-amino-ethanol which is generally known asNovocain or Procain and the vasoconstricting agent epinephrin.

There are, however, several disadvantages connected with the knownanesthetic combinations containing the vasoconstricting agent,epinephrin. For example, it has been known for a long time thatepinephrin is not ideal forthis purpose on account of the toxicby-effects which follow its use. Thus, in his Textbook of Exodontia"second edition, The C. V. Mosby Company, 1931, on page 92, Dr. LeoWinter states:

Uncomfortable and even alarming systemic reactions may occur at timesfollowing the subcutaneous administration of slightly excessive doses ofepinephrin. The patient experiences a feeling of general distress andanxiety, becomes pale and suffers from a sensation of precordial Adiscomfort and pain, and shivers more or less iting, paresthesias, andheart-burn are other symptoms which occasionally occur. As a rule, theseexaggerated and more or less alarming symptoms last only a very fewminutes and have no serious results. However, such pronounced effects onthe blood pressure and heart action may well prove harmful in cases ofhypertension, arteriosclerosis, apoplexy, aneurysm, or feeble dilatedheart.

In an article entitled Is Epinephrin Dangerous in Regional LocalAnesthesia, Dr. La Rossa and Dr. Riccio (Paris Medical, vol. 15, 1926,page 341) state that if epinephrin is to be used, cases withcardio-vascular derangements and hyperthyroidism must be excluded, andthat the patient should preferably be studied for tolerance toepinephrin by injection of small quantities of it.

Furthermore, Dr. Meeker and Dr. Frazer, (J. Pharmacol. & Exper. Therap.,vol. 22, 1923, p. 390) state:

By means of its vasoconstricting power, epinephrin (adrenalin) retardsabsorption of the anesthetic drug as well as intensifies its anestheticpower, and in that regard is a factor of safety. Certain persons,however, aside from those with hyperthyroidism, are hypersensitive toits action; in them its use should be discarded. Toxic manifestationsdue to the absorption of epinephrin (adrenalin) may be marked palpitation, a sense of oppression in the head and chest, tremor, pallor,nausea, and a sensation of fear and anxiety. No doubt the incidence ofreactions to local anesthetics would be greatly reduced were it possibleto dispense entirely with epinephrin (adrenalin) We have discovered that3.4-dihydroxy-phenyl-alpha-propanol-amine of the following formula:

HO cnon-cn-cm NH: no

can be successfully employed as a substitute for epinephrin with localanesthetic agents to localize and prolong anesthesia and much to oursurprise we have found that such combinations do not produce the abovedescribed toxic manifestations which follow the use of local anestheticcombinations with epinephrin and are tolerated without by-eifects inpatients with hyperthyroidism or heart disease and in those cases witharteriosclerosis and high blood pressure. Furthermore, we havediscovered that 10- cal anesthetic combinations with3.4-dihydroxyphenyl-alpha-propanol-amine do not produce thecollapse-like symptoms which follow the use of epinephrin in susceptiblepatients. The intensity and duration of anesthesia produced by localanesthetic combinations with 3.4-dihydroxy-phenyl-alpha-propanol-amine,employed as the vasoconstricting agent, are just as satisfactory asthose produced by local anesthetic combinations with epinephrin.

3.4-dihydroxy-phenyl-alpha propanol amine is described in U. 8. PatentNo. 1,044,778, issued November 19, 1912, as a product having thevaluable therapeutic property of increasing the blood pressure in thesame manner as the substance contained in the suprarenal glands. Thereis no disclosure in the literature concerning the use of this compoundas a substitute for epinephrin in local anesthetic combinations.

By means of clinical experiments we have determined that the intensityand duration of anesthesia produced by the injection of an aqueous 2 percent Novocain" solution containing, for instance,3.4-dihydroxy-phenyl-alpha-propanolamine 1:10,000 are approximately thesame as those produced by the injection of an aqueous Novocain solutionwith epinephrin 1:50,000.

By means of animal experiments we have determined that the intravenoustoxicity of 3.4-dihydroxy-phenyl-alpha-propanol-amine is 7 to 10 timesless than that of epinephrin. An aqueous 2 per cent Novocain solutionwith epinephrin 1:50,000 is definitely more toxic when injectedintravenously into experimental animals than an aqueous 2 per centNovocain" solution with 3.4- dihydroxy-phenyl-alpha-propanol-amine 1:10,- 000..

Our new local anesthetic combinations with the vasoconstricting agentdefined above are just as suitable for use by injection or localapplication to obtain local anesthesia as similar 10- cal anestheticcombinations prepared with epinephrin.

We have further discovered that aqueous solutions of ourvasoconstricting agent are stable provided a water-soluble reducingagent is added to the solutions to prevent deterioration.

Our new anesthetic combinations can be marketed in any of the formsusual in the pharmaceutical practice, such as a powder, a tablet or aready-to-use sterile solution in sealed glass ampules, cartridges orbottles without fear of decomposition. In addition sterile ready-touseaqueous solutions, or tablets of3.4-dihydroxyphenyl-alpha-propanol-amine can be marketed so that thesurgeon or dentist can prepare for his own use local anestheticcombinations with 3.4- dihydroxy-phenyl-alpha-propanol-amine by simplyadding the desired amount of the sterile ready-to-use aqueous solutionor the desired number of the tablets to any specified amount of 'asolution of a local anesthetic agent.

As the anesthetic agent in our new local anesthetic combinations withour vasoconstricting agent we prefer to use the monohydrochloride ofpara-aminobenzoyl-diethylamino-ethanol. Other alkamine esters ofaromatic acids which may be used as the anesthetic agent are, forexample,

. para-amino-benzoyl gamma butylamino propanol sulfate,para-amino-benzoyl-dimethylamino-methyl-butanol hydrochloride,para-butylamino-benzoyl-dlmethylamino-ethanol hydrochloride,para-amino-benzoyl-22-dimethyl-3-diethylamino-l-propanol hydrochloride,alphabutyl-oxy-cinchoninic acid gamma-diethyl-eth ylene-diamidehydrochlor and gamma-(2-methylpiperidino) -propyl-benzoatehydrochloride.

As a reducing agent in our ready-to-use aqueous solutions of3.4-dihydroxy-phenyl-alpha-propanol-amine for use with local anestheticagents or their solutions and aqueous solutions of our new anestheticcombinaHons containing, besides a local anesthetic agent, thevasoconstricting agent, inorganic water-soluble products may beemployed. Preferably, we use the salts of the sulphurous andhyposulphurous acids or their derivatives, for example, sodiumbisulfite, potassium bisulfite, sodium sulfite, formaldehyde bisulfite,sodium hydrosulfite, ace tone bisulphite, and formaldehyde sulfoxylate.The quantity of reducing agent required is relatively small and dependson the reducing agent employed. In general it is advisable toincorporate 50 milligrams to 200 milligrams in each 100 cc. of solution.

In order to more fully illustrate our invention the following examplesare given, but it is to be understood that we do not restrict ourinvention to the specific compounds and proportions recited therein.

(1) One hundred grams of the monohydrochloride of para aminobenzoyldiethylaminoethanol are thoroughly mixed with l to 2 grams of3.4-dihydroxy-phenyl-alpha-propanol amine as the hydrochloride or one ofits other watersoluble salts. The uniform mixture is marketed either inthe form of a powder or a tablet. An aqueous 2 per cent solution of themonohydrochloride of para aminobenzoyl diethylaminoethanol containing3.4-dlhydroxy-phenyl-alphapropanol-amine from 1:10,000 to 1:5.000 isobtained by dissolving 2 grams of the powder or tablets in 100 cc. ofwater.

(2) Fifty to one hundred grams of the monohydrochloride ofpara-aminobenzoyl-diethylamino-ethanol and 0.5 to 1 gram of3.4-dihydroxyphenyl-alpha-propanol-amine as the hydrochloride or one ofits other water-soluble salts, are dissolved in 5000 cc. of 'sterilewater or sterile 0.6 per cent. sodium chloride solution. Five to 10grams of sodium bisulfite are then added as the reducing agent. Thesolution is then filtered.

(3) Five to ten grams of 3.4-dihydroxy-phenylalpha-propanol-aminehydrochloride are dissolved in 1000 cc. of sterile 0.6 per cent. sodiumchloride solution. Two grams of acetone bisulfite are then added as thereducing agent. The solution is then filtered.

(4) grams of the hydrochloride ofparaamino-benzoyl-diethylamino-ethanol, 2 grams of sodium chloride, 4grams of potassium sulfate and 20cc. of a 1 per cent. solution of3.4-dihydroxyphenyl-propanol-amine rendered acid by additionofhydrochloric acid are dissolved in such a quantity of distilled waterthat the whole volume amounts to 1000 cc.

If desired, 2 grams of acetone bisulfite may be added to the solution.

(5) 10 grams of the hydrochloride of paraaminobenzoyl-dimethylaminomethylbutanol, 6 grams of sodium chloride and 0.2 gram of 3.4-dihydroxyphenyl-propanol-amine hydrochloride are dissolved in such aquantity of distilled water that the whole volume amounts to 1000 cc. 2grams of acetone bisulfite may be added to the solution.

(6) 10 grams of beta-methoxy-ethylaminobenzoicacid-beta-piperidino-ethylester-monohydrochloride, 4 grams of sodiumchloride, 2 grams of sodium bisulfite and 0.2 gram of3.4-dihydroxyphenyl-propanol-amine hydrochloride are distassium sulfatesolved in such a quantity of distilled water that the whole volumeamounts to 1000 cc.

(7) 2 grams of 4-butylamino-benzoic acidbeta dimethylamino-ethylestermonohydrochloride, 4 grams of sodium chloride, 4 grams of pond 0.2 gramof 3.4-dihydroxyphenyl-propanol-amine hydrochloride are dissolved insuch a quantity of distilled water that the whole volume amounts to 1000cc. A small quantity of sulfurous acid may be added to the solution. a

In order to prevent infection of the tissues it is essential that ouraqueous solutions of 3.4-dihydroxy-phenyl-a.lpha-propanol-amine for usewith local anesthetic agents or their solutions and the 1 aqueoussolutions of our local anesthetic combinations with our vasoconstrictingagent be sterile. We have found that sterility may be insured by fillingsterile glass ampules, sterile cartridges or sterile bottles underaseptic conditions with the freshly prepared sterile solution. Ouraqueous solutions of 3.4-dihydroxypenyl-alpha-propanolamine for use withlocal anesthetic agents or their solutions and the aqueous solutions ofour local anesthetic combinations with 3.4-dihydroxyphenyl alphapropanol-amine are preferably sterilized by means of a Berkefeld filteror by autoclaving.

We have thoroughly tested our aqueous solutions of our vasoconstrictingagent for use with local anesthetic agents or their solutions and ouraqueous solutions of local anesthetic combinations with ourvasoconstricting agent for sterility and stability. Relatively oldsolutions thereof in sealed glass ampules, cartridges and bottles haveshown no change in color and have retained their full potency.

While we have described our improvements in great detail and withrespect to preferred forms thereof, we do not desire to be limited tosuch details or forms since many modifications and changes may be madeand the invention embodied in widely diflerent forms without departingfrom the spirit or scope of the invention in its broader aspects. Hencewe desireto cover all modifications and forms coming within the scope orlanguage of any one or more of the appended claims;

We claim:

1. Aqueous solutions comprising a water-soluble salt of3.4-dihydroxy-phenyl-alpha-propano1- amine and a local anesthetic agent.

2. A sterile and stable aqueous solution of 0.5% to 1% of thehydrochloride of 3.4-dihydroxyphenyl-alpha-propanol-amine, 0.6% ofsodium chloride and 0.1% to 0.2% of acetone bisulflte, and a localanesthetic agent.

3. A water-soluble powder or tablet for use as a local anestheticcomposition and the active ingredients of which are l-2 parts of thehydrochloride of 3.4-dihydroxy-phenyl-alpha-propanolamine and 99 to 98parts of the mono-hydroxychloride ofpara-amino-benzoyl-diazole-aminoethanol.

4. A sterile and stable aqueous solution of 1% to 2% of themono-hydrochloride of para-aminobenzoyl diethyl-amino-ethanol and 0.01%to 0.02% of 3.4-dihydroxy-phenyl-a1pha-propanolamine, 0.6% of sodiumchloride and 0.1% to 0.2% of sodium bisulflte.

5. A composition of matter consisting of compressed tablets containing5-10 mgms. of 3.4-dihydroxy-phenyl-alpha-propanol-amine for use withlocal anesthetic agents or their solutions as a substitute forepinephrin to localize and prolong'anesthesia and to obviate thecollapselike symptoms which follow the use of epinephrin in susceptiblepatients.

6. A composition of a matter comprising 3.4-

dihydroxy-phenyl-alpha-propanolamine and a lo-

